Background: The TP53 Arg72Pro (rs1042522:C>G) and MDM2 SNP309 (rs2279744:T>G) SNPs of the DNA damage response pathway have been shown to affect lung cancer risk. We aimed to investigate their relationship with the clinical outcome of chemotherapy (CT). Methods: We prospectively recruited 426 consecutive patients with advanced disease (352 NSCLC and 74 SCLC, 57% metastatic) referred for chemotherapy at our institution from July 2002 to January 2006: 82% male, median age at diagnosis 63 years, 56% current and 11% never smokers, 81% receiving combined platinum CT. Median follow up time was 10.5 months. Controls were 254 medical students. We designed specific TP53 and MDM2 primers for typing both SNPs using the Pyrosequencing assay. Results: Patients genotype frequencies were: TP53 Arg/Arg 51%, Arg/Pro 40%, Pro/Pro 8%, (61%, 35%, 4% among controls, p=0.02), MDM2 T/T 37%, T/G 46%, G/G 17%, (31%, 55%, 14% among controls, p=0.07). Both groups were in Hardy-Weinberg equilibrium. At multivariable analysis adjusted for gender, smoking status, type of chemotherapy, disease stage, and side effects, survival was significantly associated with performance status (PS) [HR 1.54 (1.2–2.0)], histology [SCLC vs. NSCLC - HR 1.51(1.1–2.1)] and objective response [yes vs. no HR 0.56 (0.4–0.7)] but with neither SNP; in contrast, grade 3–4 toxicity and objective response were concomitantly associated with the SNPs of TP53 [Pro carriers vs. Arg/Arg HR 1.40 (1.1–1.8) and 1.44 (1.0–2.0)] and MDM2 [GG vs. TT 0.57 (0.4–0.9) and 0.61 (0.4–0.97)]. These findings are in agreement with the notion that MDM2 GG homozygous cells express higher levels of mdm2, thus attenuating the p53 pathway, but don’t easily fit with the alleged greater apoptotic potential of p53 Arg72. We also observed significant associations of toxicity with platinum therapy, of objective response with histology and of both outcomes with PS (not shown). Conclusion: The study provides preliminary evidence that germ-line TP53 and MDM2 SNPs affect toxicity and objective response to CT in lung cancer patients, probably depending on a variable DNA damage response but not survival time that may mainly result from the tumor aggressiveness and somatic mutational status.
MDM2 309 and TP53 Arg72Pro single nucleotide polymorphisms (SNPs) and clinical outcome in advanced lung cancer patients
NOVELLO, Silvia;MANDRILE, Giorgia;GIACHINO, Daniela Francesca;GREGORI, Dario;DE MARCHI, Mario;SCAGLIOTTI, Giorgio Vittorio
2007-01-01
Abstract
Background: The TP53 Arg72Pro (rs1042522:C>G) and MDM2 SNP309 (rs2279744:T>G) SNPs of the DNA damage response pathway have been shown to affect lung cancer risk. We aimed to investigate their relationship with the clinical outcome of chemotherapy (CT). Methods: We prospectively recruited 426 consecutive patients with advanced disease (352 NSCLC and 74 SCLC, 57% metastatic) referred for chemotherapy at our institution from July 2002 to January 2006: 82% male, median age at diagnosis 63 years, 56% current and 11% never smokers, 81% receiving combined platinum CT. Median follow up time was 10.5 months. Controls were 254 medical students. We designed specific TP53 and MDM2 primers for typing both SNPs using the Pyrosequencing assay. Results: Patients genotype frequencies were: TP53 Arg/Arg 51%, Arg/Pro 40%, Pro/Pro 8%, (61%, 35%, 4% among controls, p=0.02), MDM2 T/T 37%, T/G 46%, G/G 17%, (31%, 55%, 14% among controls, p=0.07). Both groups were in Hardy-Weinberg equilibrium. At multivariable analysis adjusted for gender, smoking status, type of chemotherapy, disease stage, and side effects, survival was significantly associated with performance status (PS) [HR 1.54 (1.2–2.0)], histology [SCLC vs. NSCLC - HR 1.51(1.1–2.1)] and objective response [yes vs. no HR 0.56 (0.4–0.7)] but with neither SNP; in contrast, grade 3–4 toxicity and objective response were concomitantly associated with the SNPs of TP53 [Pro carriers vs. Arg/Arg HR 1.40 (1.1–1.8) and 1.44 (1.0–2.0)] and MDM2 [GG vs. TT 0.57 (0.4–0.9) and 0.61 (0.4–0.97)]. These findings are in agreement with the notion that MDM2 GG homozygous cells express higher levels of mdm2, thus attenuating the p53 pathway, but don’t easily fit with the alleged greater apoptotic potential of p53 Arg72. We also observed significant associations of toxicity with platinum therapy, of objective response with histology and of both outcomes with PS (not shown). Conclusion: The study provides preliminary evidence that germ-line TP53 and MDM2 SNPs affect toxicity and objective response to CT in lung cancer patients, probably depending on a variable DNA damage response but not survival time that may mainly result from the tumor aggressiveness and somatic mutational status.
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